Reagent cabinet system

ABSTRACT

A reagent cabinet for an automated processing apparatus. The reagent cabinet has a housing, and a drawer slidably mounted in the housing. The drawer has a lower deck adapted to receive a fluid reservoir, and an upper deck located above the lower deck and adapted to receive a fluid supply container. A supply connection hose is provided to selectively connect the fluid supply container to the fluid reservoir. A reservoir connection hose is provided to selectively connect to the fluid reservoir and to convey fluid from the fluid reservoir to a downstream location outside the cabinet. A pump is mounted on the drawer. The pump is adapted to convey fluid through either the supply connection hose or the reservoir connection hose.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is related to and claims the benefit of U.S.application Ser. No. 12/622,162 filed Nov. 19, 2009 and U.S. ProvisionalPatent Application Ser. No. 61/242,694, filed Sep. 15, 2009, entitled“Automated sample processing systems and methods”, and both areincorporated by reference in their entirety.

BACKGROUND

1. Field of the Art

The present disclosure relates to automated sample processing systems,and provides systems and methods that permit high-throughput specimenprocessing for samples that may be provided in various states ofpreparation.

2. Description of Related Art

Historically, biological samples being tested in the context of medicalservices have been processed using labor-intensive manual methods, orsemi-automated methods requiring careful supervision by a laboratorytechnician. Such systems can be prone to operator error in many forms,such as improper testing (e.g., using an improper reagent or mis-readingthe results), sample loss (e.g., spilling a sample), and identity loss(e.g., losing the patient name or associating the sample with theincorrect patient). While automated and semi-automated methods may helpreduce labor costs and operator error, many automated systems arecumbersome to use. For example, many “automated” systems are actuallyonly semi-automated, and may require labor-intensive pre-processingsteps to transfer the input samples into a format, such as a particularsample container, that the machine can accept. Others perform a subsetof processing steps but require an operator to manually perform theothers, such as reagent mixing. It has also been found that existingsemi-automated systems may lack safety controls, require frequentstopping for service, operate inefficiently or slowly, or have otherproblems or shortcomings.

There exists a need in the art for alternative automated andsemi-automated processing systems, processing systems that can acceptsamples in various formats, and processing systems that cansimultaneously process different kinds of samples. There also is a needfor alternative sample processing methods. There also is a need foralternative sample processing equipment and sub-systems that may be usedto assist with sample processing tasks in fully-automated,semi-automated and manually-operated systems.

SUMMARY

The present disclosure provides a number of inventions that may be usedcollectively, in various combinations, or alone. The following summaryprovided examples of such inventions, and does not limit the inventionas claimed in any way.

In one exemplary aspect, there is provided a reagent cabinet for anautomated processing apparatus. The reagent cabinet has a housing, and adrawer slidably mounted in the housing. The drawer has a lower deckadapted to receive a fluid reservoir, and an upper deck located abovethe lower deck and adapted to receive a fluid supply container. A supplyconnection hose is provided to selectively connect the fluid supplycontainer to the fluid reservoir. A reservoir connection hose isprovided to selectively connect to the fluid reservoir and to conveyfluid from the fluid reservoir to a downstream location outside thecabinet. A pump is mounted on the drawer. The pump is adapted to conveyfluid through either the supply connection hose or the reservoirconnection hose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an isometric view of an exemplary automated sample processingsystem according to one embodiment of the invention.

FIG. 2 is a schematic top plan view of the embodiment of FIG. 1, withthe bottom of the figure corresponding to the front of the machine.

FIG. 3 is an isometric view of the embodiment of FIG. 1, shown withcertain exterior panels removed to better illustrate the structure.

FIG. 4 is an isometric view of an exemplary multi-well plate.

FIG. 5 is an isometric view of an exemplary sample rack and an exemplarysample container.

FIG. 6 is an isometric view of an exemplary control vial, and exemplaryoil container, and an exemplary rack for holding the control vial andoil container.

FIGS. 7A, 7B and 7C are isometric, top and side views, respectively, ofan exemplary reagent pack and rack.

FIGS. 8A and 8B are isometric views of an exemplary cabinet.

FIG. 9 is a flowchart illustrating an exemplary testing process.

DETAILED DESCRIPTION

The present disclosure provides various exemplary embodiments ofautomated or semi-automated sample processing systems, methods forautomated, high-throughput sample processing, control systems forcoordinating and controlling the operations of a high-throughputspecimen processing systems, and various devices that may be used in theforegoing sample processing systems or in other processes, devices orsystems. Preferred embodiments of the invention may provide faster, morereliable, and cheaper methods and machines for high-throughput patientsample processing, but other benefits may be realized instead of or inaddition to these.

FIGS. 1-3 provide various views of an exemplary automated system in theform of an analytical system (“AS”) 100. FIG. 1 is an isometric view ofthe AS 100 showing the device with its exterior coverings in place. FIG.2 is an overhead schematic view of the AS 100, generally showing thelayout of various internal parts. FIG. 3 is an isometric view withvarious panels and covers removed to better illustrate the internalparts. This embodiment of an AS 100 may be configured to perform anassay on patient samples to determine, for example, the presence orabsence of viral DNA. For example, exemplary systems may be able toperform assays for rapid and sensitive detection of high-risk humanpapillomavirus (“HPV”) types in clinical specimens. Assays associatedwith such HPV tests include, for example, those known in the digene eHRHPV DNA Test, the digene eHR HPV 16, 18/45 DNA Test, the Hybrid Capture2 assay, and the Next Generation Hybrid Capture® Assay protocolavailable from QIAGEN Gaithersburg, Inc. of Gaithersburg, Md.(“Qiagen”). Steps in such an assay may include sample loading, targetnucleic acid denaturation, probe hybridization, target capture, signalproduction, signal detection and assay result reporting. Samples used insuch assays may be processed from a so-called “pap smear” sample, fromcervical cell samples taken into a sample collection medium such asthose described in U.S. provisional application Ser. No. 61/108,687filed Oct. 27, 2008, U.S. provisional application Ser. No. 61/174,848,filed May 1, 2009, U.S. patent application Ser. No. 12/605,540, filedOct. 26, 2009, or U.S. patent application Ser. No. 12/605,605, filedOct. 26, 2009, (each of which is incorporated by reference herein), orfrom any other source of patient cells.

Embodiments of an AS 100 may provide high throughput screening assays,and may process samples for HR HPV screening, Reflex 16 18/45Genotyping, CT/GC, Group B Step, Trichomonas, Vaginosis, Cancer Dx, andso on. Exemplary assays that may be performed in embodiments of theinvention are described in U.S. Provisional Application Ser. No.61/045,952, filed Apr. 17, 2008, entitled “COMPOSITIONS, METHODS, ANDKITS FOR DETERMINING NUCLEIC ACID”; U.S. Provisional Application Ser.No. 61/113,841, filed Nov. 12, 2008, entitled “COMPOSITIONS, METHODS,AND KITS FOR DETERMINING NUCLEIC ACID,” U.S. Provisional ApplicationSer. No. 61/122,621 filed Dec. 15, 2008 entitled “AUTOMATED HPV ASSAYAND SYSTEM”; 61/147,623, filed Jan. 27, 2009, entitled “ISOTHERMALHELICASE DEPENDENT MULTIPLEX ASSAY FOR DETECTION OF CHLAMYDIATRACHOMATIS AND NEISSERIA GONORRHOEAE WITH FLUORESCENCE ENDPOINTDETECTION,” U.S. Ser. No. 12/426,076, filed Apr. 17, 2009; U.S.Provisional Application Ser. Nos. 61/108,687, filed Oct. 27, 2008,entitled “NOVEL FAST RESULTS HYBRID CAPTURE ASSAY”; 61/179,848, filedMay 1, 2009, entitled “NOVEL FAST RESULTS HYBRID CAPTURE ASSAY”; U.S.patent application Ser. No. 12/605,540, filed Oct. 26, 2009, entitled“Fast Results Hybrid Capture Assay and System”; Ser. No. 12/605,605,filed Oct. 26, 2009, entitled “Fast Results Hybrid Capture Assay On AnAutomated Platform”; U.S. Pat. No. 6,228,578, U.S. ProvisionalApplication No. 61/180,821; Tong et al., “Development of isothermalTaqMan assays for detection of biothreat organisms,” BioTechniques Vol.45, 543-557 (2008); Motré et al. “Enhancing helicase-dependentamplification by fusing the helicase with the DNA polymerase,” Gene Vol.420, 17-22 (2008); Chow et al., “Application of IsothermalHelicase-Dependent Amplification with a disposable Detection Device in aSimple Sensitive Stool Test for Toxigenic Clostridium difficile,” J.Mol. Diagnostics. Vol. 10 (5), 452-458 (2008); Li et al., “Primase-basedwhole genome amplification,” Nucleic Acids Research 36(13): e79 (2008);Goldmeyer et al., “Identification of Staphylococcus aureus andDetermination of Methicillin Resistance Directly from Positive BloodCultures by Isothermal Amplification and Disposable Detection Device,”J. Clin. Microbiol. Vol. 46, 1534-1536 (2008); Kong et al., “Newisothermal molecular diagnostic platforms,” IVD Technology Novemberissue (2007); Goldmeyer et al., “Development of a novel one-tubeisothermal RT-tHDA platform for rapid RNA detection,” J. Mol.Diagnostics. Vol. 9, 639-644. (2007); Xu et al., “Simultaneousamplification and screening of whole plasmids using the T7 bacteriophagereplisome,” NAR 34(13): e98 (2006); An et al., “Characterization of aThermostable UvrD Helicase and its Participation in Helicase DependentAmplification,” The Journal of Biological Chemistry Vol. 280,28952-28958 (2005); and Vincent et al., “Helicase Dependent IsothermalDNA Amplification,” EMBO reports Vol. 5, 795-800 (2004), the contents ofwhich are hereby incorporated by reference in their entireties.

Additionally, though laboratory protocols are often quite diverse intheir particular steps, many generally rely on various common underlyingoperations, such as the addition of reagents, mixing, incubating, and soon. Embodiments of the invention described herein may be adapted toprovide the ability to perform a diverse set of common laboratoryoperations, with different systems readily constructed from combinationsof system components described herein to perform at least a subset ofthe steps required in virtually any protocol. In addition to or insteadof measuring a sample characteristic, embodiments of the invention maybe adapted to provide a tangible output in any suitable output format,including multi-well formats, outputs to a membrane or blotting paper,bacterial, yeast or mammalian cell culture plate, and so on. The systemsprovided herein may be utilized, for example, for high-throughputpreparation of DNA, RNA, protein, plasmids, chromosomes, antibodies, ororganelles. Other systems may be used to perform all or part of methodssuch as: transformation; mating (e.g., of yeast, nematodes, or othersmall organisms); cloning; dot blotting (for DNA, RNA, protein, enzyme,etc.); mutagenesis; preparation for sequencing; nucleic acidamplification; primer synthesis; ELISA; enzyme assays; X-gal staining;immunohistochemistry; immunofluorescence; sample fixing; flow cytometry;in-situ hybridization; in vitro transcription and/or translation; samplepurification from agarose; peptide synthesis; combinatorial librarypreparation; and so on. Processes using embodiments of the invention mayemploy samples of virtually any origin including, for example:prokaryotic cells; eukaryotic cells; tissue samples from multicellularorganisms; whole organisms (e.g., flies, worms, or other similarly smallorganisms); conditioned media; environmental samples; and so on.Exemplary protocols that may be performed include those shown in thetexts “Molecular Cloning: A Laboratory Manual” (Third Edition, ColdSpring Harbor Press) or “Condensed Protocols From Molecular Cloning: ALaboratory Manual” (First Edition, Cold Spring Harbor Press), thedisclosures of which are hereby incorporated by reference in theirentireties. In addition, as explained below, the AS 100 may beconfigured and programmed to perform various different assaysessentially at the same time, where multiple different sample types areinput into the system at the same time.

A central control unit (CCU) may be used to control and/or monitor theAS 100. The CCU may be a dedicated software controller for the AS 100, amulti-system controller that monitors or oversees operation of the AS100 an upstream pre-analytical system (“PAS”) or other devices, or anycombination of control, monitoring or reporting systems. An example of apre-analytical system that may be used to prepare samples, such assamples provided in standard 96-well sample plates described below, isdescribed in U.S. application Ser. No. 12/588,304, filed on Oct. 9,2009, which is incorporated herein by reference. An exemplary CCU mayprovide a processing interface between the AS 100 and the PAS. Forexample, a CCU may be combined with an AS 100 and a PAS to perform allof the steps necessary to pre-process and test a sample according to theHybrid Capture 2 or Next Generation Hybrid Capture® protocols. Anexemplary CCU may have features such as those described in U.S.Application No. 61/262,497 filed Nov. 18, 2009, which is incorporatedherein by reference in its entirety.

The exemplary AS 100 is a generally self-contained unit having variousinput and output locations at which an operator can provide supplies andremove waste and processed samples. The AS 100 may be enclosed in ahousing 124, which may have a window 126 through which an operator canobserve the operation of the machine. While the shown AS 100 is astand-alone unit, alternative embodiments may partition various parts ofthe machine into separable modules, or integrate the machine into alarger processing system.

In the exemplary embodiment, the AS 100 includes a first sample bay 102,a second sample bay 104, a control bay 106, a pipette tip input 108, areagent bay 110, and one or more solid or liquid waste outputs (notshown). The functions of these various inputs and outputs are describedin more detail below. The AS 100 also may include a suitable electricalinterface (not shown) for connecting to a CCU that controls the device.Of course, the CCU, or various parts of it, may be integrated into theAS 100 itself, in which case the AS 100 may be provided with a humaninterface to receive operating instructions and/or display systemstatus. Such an interface may include various interface elements knownin the art, such as a monitor, touch-screen monitor, keyboard, mouse,microphone, speaker, barcode reader, and so on. While the shownarrangement of inputs and bays has been selected for this embodiment, itwill be understood that other arrangements may be used in otherembodiments.

The first sample bay 102 is adapted to receive samples, such asliquid-based cytology (LBC) samples, that are provided as collections ofsamples on sample plate. Each sample plate may include one or morepatient samples. The first sample bay 102 has a number ofvertically-stacked tracks 112 (e.g., fifteen tracks), each of whichreceives one plate. In the exemplary embodiment, the first sample bay102 receives plates from a user, and returns the plates to the user forremoval once processing is complete. The tracks 112 preferably can beindividually loaded and unloaded with plates during operation of themachine, to provide a substantially continuous supply of first samplesfor processing.

To prevent confusion, lights 114 or other indicators may be providedadjacent each track 112 to indicate the status of the plate associatedwith that track 112. For example, a green light may indicate that atrack is free to receive a plate, or that a plate in that track is freeto be removed. An orange light may indicate that the plate in that trackis queued for processing and can not be removed. A red light mayindicate that an empty track should not be filled with a plate because aplate currently being processed is intended to be replaced in thatparticular track. Other colors and flashing lights may be used toindicate additional status situations.

Locks also may be provided on the tracks 112 to prevent improper removalor insertion of plates. In addition, a door (not shown) may be providedto enclose the first sample bay 102 when it is not being used. It willbe appreciated that many variations may be made to the foregoingexemplary embodiment. For example, the first sample bay 102 may compriseseparate plate input and output locations, the tracks may be arranged indifferent orientations, and so on. These and other variations may alsobe applied to the other tracks, supplies and loaded components describedbelow.

An example of a first sample plate that may be used in the first samplebay is shown in FIG. 4. In this embodiment, the plate comprises astandard 96-well plates 400, such as shown in FIG. 4, may be used tosupply up to ninety-six samples each at the first sample bay 102. Asshown in FIG. 4, each 96-well plate 400 includes a plate frame 402 and anumber of wells 404. A separate sample may be placed in each well, and aplate sealer may be used to seal the plate to help preventcross-contamination and evaporation. An exemplary 96-well plate is theGreiner 96-well microplate available from Greiner Bio-One GmbH ofFrickenhausen, Germany. These and other plates, as well as platesealers, are well-known in the art and need not be described here. Ifthe chosen sample plate lacks structural features by which it can bemanipulated as desired by the AS, the sample plates may be mounted incarriers, such as carrier 406, that hold the plate and providemanipulation points to enhance the AS's ability to manipulate the plate.The shown carrier 406 includes a perimeter frame 408 to retain the plate400, an opening 410 to provide access to the bottom of the plate 400,and a manipulation track 412 having openings 414 to receive a toothedmoving arm. An exemplary moving arm (not shown) may have teeth that fitinto the openings 414 to push and pull the carrier 406 and plate 404.Such devices are known in the art and available, for example, fromStratec Biomedical Systems AG of Germany.

Though this example is described using 96-well plates, embodiments mayreadily be adapted for processing samples in another multi-well plateformats (e.g., 6-well, 12-well, 24-well, 48-well, 384-well or 1536-wellplates, or other multi-well plate formats).

The AS 100 preferably also includes a second sample bay 104 to receivesamples which may be in a different format than those provided in thefirst sample bay 102. In the exemplary embodiment, the second sample bay104 comprises a series of side-by-side tracks 116 that are locatedremotely from the first sample bay 102. These tracks 116 are adapted toreceive samples provided on a sample rack, such as shown in FIG. 5. Therack 500 may be a conventional design, having a rack body 502 withmultiple wells 504 that are each adapted to hold a sample container 506.A handle 508 may be provided at one end of the rack 500, and a groove510 may be provided to receive the track 116 to guide and orient therack 500 as it is installed. Such rack and track systems are known inthe art, and need not be described in further detail herein. While theshown rack 500 holds samples in a linear array (i.e., in a single row),alternative racks may hold sample containers in a two-dimensional array.The wells in such an array may be in a square pattern (as in the sampleplate 400), staggered, in a radial pattern, or in any other suitablepattern. An example of a sample container rack having a two-dimensionalwell array is shown in U.S. application Ser. No. 12/622,150 entitled“Sampling Devices and Methods” filed on Nov. 19, 2009, which isincorporated herein by reference. Such a rack may hold a single kind ofsample, or multiple different sample types.

The second sample bay 104 may include locks and/or status indicators(such as lighted LEDs) to help regulate the insertion and removal ofsamples. If desired, a door (not shown) may be proved over the secondsample bay 104. The racks 500 preferably can be individually loaded andunloaded during operation of the machine, to provide a substantiallycontinuous supply of second samples for processing.

The sample rack 500 may hold samples provided in one more differentkinds of sample container. For example, the rack 500 may hold samplesprovided in the shown exemplary sample tube 506. The sample container506 may comprise a tube body 512 and a removable cap 514. Many differentkinds of sample container 506 may be used. For example, the samplecontainer 506 may comprise a liquid-based cytology container for holdingcervical samples, a urine vial, a blood vial, and so on. Many differentshapes and sizes of such containers are known, and the rack 500 can bemodified to fit any typical container, as desired.

The sample rack 500 may be modified, as desired, in other embodiments.For example, the rack 500 may have one or more barcodes on it, and mayhave cutouts along the side of each well 504 so that a barcode readercan scan a barcode provided on each sample container 506 as the rack 500is being moved along the track 116. Barcodes may be used to identifyeach sample and associate each sample with a rack position, anddouble-check that each sample is intended to be used in the assay beingconducted in the AS 100. Other uses for barcoding may also be apparentto those of ordinary skill in the art.

The rack 500 and sample containers 506 also may include features, suchas pierceable caps and magnets on the rack and magnetic brushes in thecontainers, to facilitate the pipetting operations described herein.Examples of such magnetic features are described in U.S. applicationSer. No. 12/622,150 entitled “Sampling Devices and Methods” filed onNov. 19, 2009. Another exemplary feature that may be used with thesecond sample bay 104 is a retainer panel 118 located above the tracks116 and racks 500. The retainer panel 118 has openings above each samplelocation when the racks 500 are installed, to allow access to eachsample container. In addition, the retainer panel 118 may be modified tohold the sample containers in place to prevent pipette tips (or otherdevices that may be inserted into and withdrawn from the samplecontainers) from lifting the sample containers out of the racks 500. Anysuitable construction for a retainer panel 118 may be used, and in oneembodiment, the retainer panel 118 comprises a stepped or ramped designthat helps reduce the likelihood that sample containers will becontaminated as they are installed or removed from the second sample bay104. Examples of such a retainer panel 118 are described in U.S.application Ser. No. 12/622,140entitled “Sample Vial Retainer” filedNov. 19, 2009. The foregoing two applications are incorporated herein byreference in their entireties.

In one exemplary embodiment, a process for loading racks 500 havingsamples containers may include sliding the racks into the second samplebay 104, and using a CCU and scanner to scan barcodes on each rackand/or sample container as they are being slid into place. If all of thebarcodes are not successfully scanned, the rack is removed, and thesamples may be rearranged to better present their barcodes to thescanner, or they may be manually scanned or entered into the system byother means, such as manual alphanumeric input. Once the data for eachsample and rack is captured by CCU, the CCU determines the work schedulefor each sample (e.g., the assays to be run, and whether a subsequentreflex assay will be performed is a positive result is obtained). Thework schedule may be obtained from a CCU, user input, an indicatorassociated with a sample, other known means, or combinations of theforegoing. For example, if a sample is provided for which the softwarecontroller has not received a work order, a user may be prompted toindicate whether an assay is ordered. The CCU then confirms that eachsample calls for the assays or tests for which the AS 100 is configured(e.g., with respect to the reagents and buffers), and confirms thatsufficient system resources are available to conduct the necessary stepsbefore initiating processing.

The exemplary control bay 106 is located next to the second sample bay104, although other locations may be used in other embodiments. Thecontrol bay 106 is provided for the addition of control and/orcalibration samples that may be selectively used by the AS to confirmproper operation. Examples of control and calibration regimes aredescribed in more detail below. The control and calibration samples canbe provided in any suitable form. For example, FIG. 6 illustrates anexemplary control rack 600 that may be used to provide control andcalibration samples that are provided in vials similar to the samplecontainer 506 described above. In particular, the control andcalibration samples may be provided with pierceable caps, so that theoperator is not required to open them before placing them in themachine. While pierceable caps are preferred in some instances, otherembodiments of the AS 100 may use containers with machine-removable caps(such as twist-off caps or pushcaps) that are automatically removed toprocess the container's contents. Examples of twist-off caps andpushcaps include those shown in U.S. application Ser. No. 12/588,304filed Oct. 9, 2009 (showing a decapping unit to remove twist-off caps)and U.S. application Ser. No. 12/616,899 filed Nov. 12, 2009 (showing amachine-removable pushcap). The foregoing references are incorporatedherein by reference in their entireties. In still other embodiments, thevarious containers may simply use hand-removed caps or covers over thevarious samples, reagents, controls, calibrators and so on.

In the exemplary embodiment, the control rack 600 is similar to thesecond sample rack 500 described above. In particular, the control rack600 includes a rack body 602 having multiple control wells 604, each ofwhich includes a slot 606 through which a barcode on each control can beread. Barcoding can be used to identify the controls, ensure they areproperly positioned, and so on. Barcodes between each adjacent pair ofwells 602 may be used to associate each control with a particular well.A reader (not shown) located at one side of the control bay 106 toproject a reading beam along the width of the bay 106 can read eachbarcode as the rack 600 is installed. The control racks 600 also mayinclude a track 614, like the track 510 on the sample rack 500, toorient and guide the rack 600 in the AS 100.

As shown, one exemplary embodiment of a control rack 600 may include sixcontrol wells 604. In this embodiment, two of the wells are used forpositive controls 610, two are used for negative controls, and two areused for calibrators. To further reduce the likelihood of error, thecontainers in which the controls and calibrators are provided may becolor-coded to match particular designated wells 604. The control rack600 also may hold reagents, patient samples, or other consumables usedby the AS 100. For example, the control rack 600 may include twoadditional wells 608 adapted to receive oil packages 612. Oil in thesepackages 612 may be used, for example, to cover the patient samples asthey are processed to help reduce evaporation during incubation,testing, processing or storage. Reagents also may be provided in thecontrol rack 600. The control racks 600 preferably can be individuallyloaded and unloaded during operation of the machine, to provide asubstantially continuous supply of controls, calibrators, oil and so onto the machine.

Locks or status indicators may be provided to help regulate when controlracks 600 may be inserted into and removed from the control bay. Also, aretainer panel 118, such as described above, may be positioned over thecontrol bay to retain controls, calibrators, oil packages, and whateverother containers may be used in the control racks 600.

An exemplary process for loading controls and calibrators into the AS100 may include loading controls, oil and calibrators onto racks 600,sliding one or more filled control racks 600 into the control bay 106,and scanning them as they are being slid into place. A CCU checks thescanned barcode data, and determines whether the controls, calibratorsand oil are valid (e.g., not expired, not previously used and depleted,the proper controls/calibrators/oil for the particular tests being run,etc.). The CCU also may initiate a test count to determine the number oftests that can be performed using the supplies, optimize the number oftests, store the number of test for use during processing, and displaythe number of tests to an operator on a graphical user interface. Ofcourse, other loading processes may be used in other embodiments.

Referring to FIGS. 1 and 3, the pipette tip input 108 is provided toload unused pipettes into the AS 100. This input 108 may be on the frontof the machine, but other locations are possible in other embodiments.The pipette tip input 108 may comprise any suitable arrangement forloading unused pipette tips into the AS 100. In the shown embodiment,the pipette tip input 108 comprises multiple drawers that hold pipettetip racks. Each rack includes a number of holes into which unusedpipette tips are placed. When the drawers are closed, the pipette tipsare oriented vertically, and accessible by one or more automatedpipettors through one or more openings 120. If desired, different kindsof pipette tips may be provided in different drawers. For example, wheredifferent assays to be run simultaneously require different pipettetips, tips appropriate for both assays may be loaded and the systemprogrammed to use the appropriate tips for each assay. The design ofsuitable pipette tip drawers is known to persons of ordinary skill inthe art and need not be described herein. If desired, the drawers may beprovided with locks and indicators, such as LED lights 123, to ensurethat the drawers are not opened as pipettes are being withdrawn from theracks. Such lights also may indicate status, such as: locked orunlocked, ready for loading, empty, or in-use. A CCU associated with theAS 100 also may be programmed to indicate to the user when all of thedrawers are full, indicate the number of tests that can be run with theavailable tip supply, provide real-time monitoring of the drawers, andso on.

The reagent bay 110 also may be located on the front of the AS 100, orelsewhere as desired. Like the second sample bay 104, the reagent bay110 may comprise a number of rails adapted to receive reagents providedon racks. To ensure that racks are not improperly loaded, the racks forthe second sample bay 104, control bay 106, and reagent bay 110 may beconstructed such that they are not interchangeable (e.g., by providingdifferent track shapes for each kind of bay and rack). Each track mayhave a lock or a light to help regulate access to the racks. Forexample, a multicolor LED may be provided to illuminate green to signalthat a rack is empty and unassigned to the system resources, red tosignal that a rack is loaded but not yet assigned to the systemresources, or orange to indicate a loaded and properly assigned reagentrack.

Referring now to FIGS. 7A-7C, reagents may be provided in individualcontainers or in one or more reagent packs 700. The shown exemplaryreagent pack 700 includes multiple reagent reservoirs 702, each of whichcontains a reagent 704. A single reagent pack 700 may include allreagents necessary to perform a given assay, but this is not required. Aseal 706 covers openings 708 at the top of each reagent reservoir 702.The seal 706 may be made of a pierceable material, such as a foil,plastic film, etc. that can be penetrated by a robotically actuatedpipette to gain access to the reagents 704 during use. Each reagentreservoir 702 may be sized to receive one or more pipettes, such as theshown embodiments which are sized to receive two pipettes at a time. Ifmixing of reagents is necessary, an automated pipettor may draw reagentsfrom one reservoir and mix them with reagents in another reservoir.In-place mixing to ensure the reagents are homogeneous may also be doneusing shaker or, more preferably, by repeatedly drawing reagent into apipettor and depositing it back into the reservoir (i.e., mixing byso-called “pipetting action”).

The reagent pack 700 is held in a reagent rack 701 that is adapted toslide into the reagent bay 110. The reagent rack 701 may be constructedin any suitable way. For example, in a preferred embodiment the rack 701is built similarly to the racks described above with respect to FIG. 5or 6, with a track to orient and hold the rack 701 as it is slid in andout of a corresponding track in the reagent bay 110, a bar code toidentify the specific rack 701, and one or more barcodes to identify thereagent reservoirs being loaded into the AS 100. The racks 701preferably can be individually loaded and unloaded during operation ofthe machine, to provide a substantially continuous supply of reagents.Also, reagent packs 700 having reagents for multiple different assaysmay be loaded at the same time, if desired.

The reagent reservoirs 702 are affixed to a common frame 710.Alternatively, the reagent packs 700 may be made of a single integrallymolded piece comprising multiple reagent reservoirs 702 and an integralframe 710. The frame 710 includes a flexible cover 712 that covers oneor more of the reagent reservoirs 702. The flexible cover 712 issituated above the seal 706 in the depicted embodiment, though otherspatial arrangements are contemplated. For example, a flexible cover maybe situated below a seal, or a reagent reservoir may include a flexiblecover or a seal, but not both. The flexible cover 712 defines flexibleflaps 714 above each reagent reservoir 702, with each pair of flapsadapted to accommodate insertion of a pipette tip. The flexible flaps714 provide partial re-covering of the reagent reservoirs 702 after apipette tip is inserted and removed, helping to reduce the rate ofevaporation and decrease the likelihood of reagent contamination.Additionally, the flexible flaps 714 may sweep the sides of a pipettetip as it is withdrawn, helping to dislodge any liquid that is clingingto the outside of the pipette tip and cause such liquid to drop backinto its reagent reservoir 702. Each flexible flap 714 may include asmall notch or indentation 716 at the mid-line of flexible cover 712.The indentation 716 tends to keep flexible flap 714 centered on apipette tip as it is inserted or removed from the reagent reservoir 702.

In the depicted embodiment, the rightmost reagent reservoir 702 isprovided with a mixing station 720. The mixing station 720 comprises aconcentrated reagent reservoir 722 and a well 724 that may surrounds orpartially-surround the concentrated reagent reservoir 722. A cover, suchas a pierceable foil cover (not shown), may be provided over the mixingstation. Initially, a concentrated reagent is contained in theconcentrated reagent reservoir 722. Some or all of the concentratedreagent can then be drawn from concentrated reagent reservoir 722 andmixed with a diluent in the well 724. The diluent can be provided in thewell 724, or dispensed there from one of the reagent reservoirs 702 orfrom another source. For example, in one embodiment, the diluent isprovided in the right-most reagent reservoir 702. In this embodiment, atleast some of the reagents may be prepared by withdrawing some of thediluent from the reservoir 702 and depositing this diluent into the well724. Next, the concentrated reagent is drawn from the concentratedreagent reservoir 722, deposited into the well 724, and mixed with thediluent by, for example, pipetting action or shaking the reservoir. Thispartially-diluted concentrated reagent can then be drawn into thepipettes, deposited into the right-most reagent reservoir 702, and mixedagain to fully dilute the concentrated reagent. The use of the foregoingor similar processes is expected to save a significant amount ofoperator time over conventional systems, which typically require manualmixing of reagents before operation. Additionally, automated mixing ofreagents may be performed in advance of the expected time forcommencement of sample processing, such that the machine will be readyto commence sample processing without incurring any delay for reagentmixing. For example, reagent mixing may be started at the end of a workshift, at a pre-set time during a period of inactivity, manually at thestart of a work shift, or in response to another triggering event.

In an exemplary embodiment, the reagent reservoirs 702 may contain adenaturation reagent, detection labeled antibodies, bead suspensions,detection reagents, diluents, and/or nucleic acid probes (such as RNA,DNA, and synthetic nucleic acid analogues, etc.). When a reagentcomprises a suspension such as magnetic beads or another reagentsusceptible to settling or separation, periodic mixing may be performedby pipetting action or other known means. For example, an initial mixingprocedure involving multiple cycles of aspiration and dispensing may beperformed when the reagent pack 700 is first put into use or is usedafter an extended period of non-use. Subsequently, additional mixing,which may be less extensive than initial mixing, may be performed priorto each use or at a predetermined interval (e.g., after a fixed periodof time has elapsed since the last time the reagent was mixed or used).To minimize inefficiencies, such intermediate mixing may be scheduledwhile other processes are running.

Because the volume of a reagent will decrease as the reagent isconsumed, the volume aspirated and dispensed during pipettor mixing canbe varied accordingly to ensure adequate mixing of the remaining volume.For example, aspiration volume may be 20% of the calculated remainingreagent volume—i.e., volume=(number of tests remaining)*(volume pertest)*0.20. A lower boundary on the aspiration volume can be used toensure that the volume is sufficient for adequate mixing. Accommodatingthis lower boundary on aspiration volume may be accomplished using areagent reservoir that is “overfilled” such that there is alwayssufficient volume remaining for adequate mixing to be performed.Alternatively, resuspension may not be attempted if the reagent volumeremaining is below a defined cutoff volume; rather, if resuspension isrequired (e.g., due to elapsed time), it would not be attempted andinstead the reagent pack would have to be discarded. In still anotherembodiment, reagent from a nearly expired pack that can no longer besuitably mixed may be aspirated and combined with a new reagent pack,however such a practice may be limited to circumstances in which the tworeagent packs correspond to a common production lot, calibrationprofile, or other control variable to ensure that cross-use of reagentdoes not adversely affect performance. One of skill in the art canreadily determine a minimum volume for aspiration/dispense to achievesufficient mixing for a given reagent and implement reagent-conservingsystems as described herein.

One or more sensors may be provided to detect the levels of the reagents704. Known ultrasonic sensors or other kinds of sensors may be used tocheck the fluid levels. In addition, sensors such as light detectorslocated in the reagent reservoirs or in hoses downstream of the reagentreservoirs 702 may be used to determine the presence of bubbles or airpockets in the fluid.

The reagents packs 700 may be loaded into the AS 100 using any suitableprocess. For example, the reagent packs 700 may be brought to roomtemperature (if refrigerated), loaded into corresponding racks 701, slidonto a rack in the reagent bay 110, and scanned as it is slid intoplace. A CCU determines whether the reagent pack 700 is valid (e.g., theproper reagents for the intended assay, not expired, not previously usedand consumed, etc.), and initiates a mixing sequence if the reagent pack700 is valid. The CCU also may evaluate the reagent pack 700 todetermine the number of tests that may be performed using that pack or acollection of packs loaded in the AS 100, identify a reagent useprocedure to maximize the total number of tests, store the test countfor use during processing, and display the test count to the operator.Of course, other loading processes may be used in other embodiments.

The housing 124 may be mounted on a carriage (not shown) that may act asa storage cabinet for supplies, and may be operatively connected to thehousing 124 to provide supplies during operation. For example, thehousing 124 may be mounted on a carriage that contains wash buffers andone or more storage containers for solid and liquid waste. Alternately,where no biohazardous fluid or other controlled waste are generated bythe AS 100, the fluid waste can be directed to a sink. Such a carriagemay be movable on casters or wheels, and locked in place using wheellocks or legs that can be lowered into engagement with the floor. Thedesign of combined carriage and storage cabinets is known in the art,and need not be described here in detail.

The housing 124 may be mounted on a carriage (not shown) that may act asa storage cabinet for supplies, and may be operatively connected to thehousing 124 to provide supplies during operation. For example, thehousing 124 may be mounted on a carriage that contains wash buffers orreagents and one or more storage containers for solid and liquid waste.Alternately, where no biohazardous fluid waste are generated by the AS100, the fluid waste can be directed to a sink. Such a carriage may bemovable on casters or wheels, and locked in place using wheel locks orlegs that can be lowered into engagement with the floor. The housing 124alternatively may be operated as a bench-top unit. A bench-top unit mayhave all of the necessary fluid supplies and waste containers integratedinto the housing 124, or fluid supplies and containers may be providedas separate units or containers.

An exemplary embodiment of a cabinet for mounting the housing 124 isillustrated in FIGS. 8A and 8B. The cabinet 800 may comprise a frame 802formed of welded box tubes, to which various panels 804 are attached toform an enclosure. The front of the cabinet 800 may be closed by one ormore pivoting doors 806 having suitable closures. A space 808 may beprovided in the cabinet to hold a computer processing unit (CPU), suchas a typical desktop computer, and a stand 810 may be provided to hold alaptop-style CPU, a keyboard, monitor, mouse, or other accessorydevices. Features may be provided on the top of the cabinet 800 toengage and hold the housing 124. Standoff bars 812 may be provided toprevent the cabinet 800 and housing 124 from being placed too close to awall. Adjustable feet 814 are provided on the bottom of the cabinet 800,and rollers or casters may also be provided to facilitate movement.

In prior cabinet designs, the cabinet typically included one or morespaces for holding fluid bottles and waste containers. In some cases,replaceable supply bottles and containers were held on drawers, andthese supplies fed into a reservoir mounted in the cabinet, but off thedrawer. While functional, it could be inconvenient in such designs toaccess the reservoirs, and in may not be possible in these or otherdesigns to continuously refill the reservoirs while the equipment wasoperating. To help alleviate these problems, the exemplary cabinet 800may include a drawer 816 having a lower deck 818 adapted to hold fluidreservoirs 820, and an upper deck 822 adapted to hold fluid supplycontainers 824. In the shown embodiment, there are two fluid reservoirs820, and two fluid supply containers 824. The reservoirs 820 andsupplies 822 may hold the same fluid, or they may hold two fluid supplycontainers, such as a wash buffer having detergent, and a second washbuffer not having a detergent. Where the fluid supply containers 824hold different fluids, the containers, upper deck and hoses may becolor-coded, provided with unique connections or shapes, or otherwiseconfigured to help prevent them from being attached to the wrongreservoir. The upper deck 822 may include lower openings 826 to receiveoutlets from the fluid supply containers 824, as well as hose hooks 828to hold hoses 830 when the fluid supply containers 824 are not in place.One or more pumps 832 are mounted to the drawer to regulate flow fromthe fluid reservoirs 820 to the rest of the AS 100.

In the embodiment of FIGS. 8A and 8B, the fluid reservoirs 820 areconveniently refilled by opening the cabinet doors 806, sliding out thedrawer 816 using an integrated handle 834, attaching fluid supplycontainers 824 to the hoses 830, mounting the fluid supply containers824 to the upper deck 822, sliding the drawer 816 back into the cabinet800, and closing the doors 806. Using this arrangement, the hosesconnecting the supplies to the reservoirs can be relatively shortbecause it does not need to extend from a reservoir in the housing to asupply outside the housing, which helps prevent the likelihood ofcrimping or catching the hose as the supply is placed in the cabinet.This arrangement also allows an operator to more easily remove, replaceand check fluid levels in the reservoirs. Providing the pump or pumps inthe drawer also facilitates maintenance by locating all of the workingparts associated with the reservoirs in a single, accessible location.

The fluid supply containers 824 may have barcodes or other identifiersthat are read as they are loaded into the cabinet 800. A CCU associatedwith the system may check data associated with the barcodes to ensurethat the fluid supply containers 824, such as wash buffers, are valid(e.g., not expired, the proper supplies for the test being run, notpreviously used and consumed, etc.), calculate the number of tests thatmay be run with those supplies, and convey this information for use bythe system or user.

The drawer 816 also may include a bay to hold one or more liquid wastecontainers 836. In the shown embodiment, there are two liquid wastecontainers 836. Each liquid waste container 836 includes a level gauge,as known in the art, to determine when the container is filled. Incontrast to typical prior systems, however, a valve is used toselectively connect one waste container or the other to the AS 100, sothat the container that is not being filled can be removed and emptied.This helps extend the operation time of the AS 100, without requiring alarge waste container that might be difficult for the operator to removeand empty. The liquid waste containers 836 conveniently are mounted onthe same drawer 816 as the fluid reservoirs 820. This arrangementprovides enhanced ease of use and accessibility to all of the fluidcomponents contained in the cabinet 800. This arrangement also allowsall of the plumbing features (pumps, hose connections, valves, etc.)located in the cabinet 800 to be mounted on a single platform, whichmakes assembly and maintenance significantly more convenient than inconventional designs. In addition, all of the hoses leading from thedrawer 816 can be collected at the drawer making it easier to bundle thehoses to route them collectively to the rest of the AS 100. Also in thisarrangement, the hoses can be held collectively by a single hoseretainer, such as an elastic cord or spring that holds the collectedhoses up and out of the path of the drawer 816. While the foregoingarrangement is preferred, this is not required in all embodiments, andin other embodiments they may be mounted on one or more additionaldrawers, or simply held in the cabinet 800.

One or more solid waste containers 838 also may be mounted on the drawer816. in the shown embodiment, the solid waste container comprises asimple bin that may be sized to receive a conventional plastic trash bagor other removable waste container. As with the liquid waste containers836, the solid waste container 838 may be mounted on a separate drawer,or simply mounted in or beside the cabinet 800. The solid wastecontainer 838 may be mounted below a waste passage 840 that joins acorresponding waste passage 232 (FIG. 2) or opening to receive usedpipette tips or other solid waste. To facilitate continuous operation ofthe AS 100 even when the drawer 816 is open, a sliding cover 842 may beprovided between the solid waste container 838 and the waste passage840. The sliding cover 842 is mounted on a rack above the solid wastecontainer 838, and stops are placed on the various parts to slide thecover 842 in place between the solid waste container 838 and the wastepassage 840 when the drawer 816 is opened, and slide the cover 842backwards out of the way when the drawer 816 is closed. When the drawer816 is open, pipette tips and other solid waste collect in anintermediate reservoir 844 in the passage 840 above the cover 842, andwhen the drawer 816 is closed the collected waste falls into the solidwaste container 838.

Referring now to FIGS. 2 and 3, further details of the operatingcomponents of the exemplary embodiment are disclosed. As noted above,the housing 124 generally contains the working parts of the AS 100. Thefirst sample bay 102, second sample bay 104, control bay 106, pipettetip input 108, and reagent bay 110 may be aligned generally in a row,such as shown, so that access is provided along the front of the AS 100.The first sample bay 102 (shown empty in FIG. 2) is open to the front ofthe machine, and opens rearward to a traversing channel 202 that extendsbehind the various input areas (102, 104, 106, 108 and 110). A platemover 204 is provided in the traversing channel 202. The plate mover204, which may comprise any suitable robotic device or devices, isconfigured to move laterally and vertically within the traversingchannel 202 to move the sample plates 206 (two are shown) betweenvarious processing stations. If desired, multiple plate movers or othermanipulation devices may be used on other embodiments. An example of aplate mover 204 comprises a lateral movement motor 208 that moves thedevice along a track in the traversing channel 202, an elevator platform210 that is mounted to the lateral movement motor and provided with asuitable elevator motor, and one or more extension sliders (not shown)that move the plates 206 onto and off of the elevator platform. Suitabletraversing, elevating and sliding mechanisms are known in the art, andavailable from Stratec Biomedical Systems AG of Germany. The particulardetails of such motors, elevators and other movement equipment do notform a part of the present invention, and no further discussion of suchdevices is necessary here.

One or more sample preparation stations may be provided along thetraversing channel 202. In the shown embodiment, a first preparationstation 212 is located between the reagent bay 110 and the traversingchannel 202, and a second preparation station 214 is located behind thepipette tip input area 108, and next to the control bay 106. Eachpreparation station 212, 214 includes a flat platform onto which a plate206 can be placed by the plate mover 204, and may include one or moreplate locks or grips adapted to hold the plate 206 against unwantedmovement. The preparation stations 212, 214 may be include a heating orcooling block to elevate, decrease, or maintain the temperature of thespecimens located in the plate 206. As noted above, the plates 206 maybe mounted on carriers (not shown) that facilitate plate movement andhandling. The plates 206 may be moved onto the sample preparationstations with such a carriage, or separately therefrom. The preparationstations are provided to hold sample plates 206 during samplepreparation steps, such as reagent dispensing, aspiration, mixing and soon. For example, plates 206 at the first preparation station 212 may beprocessed by adding reagents, and plates 206 at the second preparationstation 214 may be processed by adding controls or calibrators from thecontrol bay 106 or by adding samples from the second sample bay 104. Ifdesired, both preparation stations 212, 214 can be integrated into asingle station. A processing station also may be used to simply hold aplate while other operations are being performed.

One or more pipettors or other devices may be mounted within the housing124, and adapted to move through the housing 124 to perform variousoperations necessary to process the samples. In the shown embodiment,two four head pipettors 216 are provided. Each pipettor 216 comprisesfour pipetting heads, each of which may have an independent pump andcontrol system so that they can operate independently with respect topipetting operations. The pipettor heads are fixed relative to oneanother, but if desired, the pipettors 216 may comprise a so-called“varispan” arrangement, in which the width between the pipettor tips canbe varied. Suitable pipettors are known in the art, and available, forexample, through Stratec Biomedical Systems AG of Germany.

Where the pipettors are spaced at a fixed distance, the distance betweenthe pipettors and the spaces between the various components and suppliesmay be selected to facilitate the universal use of the pipettes acrossthe various features. For example, the pipette tips may be spaced adistance corresponding to approximately a whole multiple of (such astwice) the distance between adjacent wells on a standard 96-well plate.In this embodiment, the reagent packs may be spaced to accommodate oneor two pipette tips in each reagent reservoir, the second samplecontainers may be spaced to each receive one pipette tip, and so on. Toprovide greater flexibility, the pipette tips may having separatevertical drive motors to permit them to be individually raised andlowered.

The first and second pipettors 216 each may be mounted on a guide arm218 that runs along a lateral track 302, and lateral movement may becontrolled by a number of belts 220 and one or more associated motors304. In this embodiment, two of the belts (one at the front and one atthe back of the housing 124) operate to traverse the first pipettor 216,and the remaining two belts traverse the second pipettor 216. Similarly,each pipettor 216 may be movably mounted on a longitudinal rack 222 thatextends in the fore-aft direction (perpendicular to the lateral track302), and movement in the longitudinal direction may be controlled by amachine screw 224 that is rotated by an associated motor (not shown).

In the shown exemplary embodiment, two four-head pipettors 216 may besufficient to perform all of the desired processing steps for variousdifferent assay protocols. One pipettor 216 may be used for operationsat one side of the housing 124, and the other may operate at the otherside of the housing 124. In other embodiments other arrangements ofsingle- or multiple-head pipettors may be used. For example, a singlepipettor may be used, or pipettors may be mounted on differentarticulating systems, such as robot arms and the like. As noted before,pipette tips are stored in drawers 122, and accessed by the pipettors216 through openings 120 through a panel over the drawers. Any suitablemechanism may be provided to connect new pipette tips to and disconnectused pipette tips from the pipettors 216. The details of the pipettorheads and tip attachment and ejection mechanisms are known in the art,and need not be described here. For convenience, a waste passage 232 maybe provided in the housing 124 to provide a passage to a solid wastecontainer 838 (FIGS. 8A and 8B) located in a cabinet 800 (FIG. 8) belowthe housing 124.

The exemplary AS 100 also may include an incubator station 226 adaptedto receive one or more plates 206. An exemplary incubator station 226may comprise a number of stacked incubator chambers (e.g., tentemperature-controlled plate slots) into which the plates 206 areselectively placed to perform various processing steps. One or more ofthe incubator chambers may include a shaker to shake the samples duringincubation. To help improve assay performance, it may be desirable toshake the samples in a series of shaking and pause cycles, but this isnot required. A typical shaker may have multiple configurableparameters, such as speed, upper and lower speed range, acceleration anddeceleration rates, shake time, and pause time. The system may beadapted to detect and verify that shaking is being performed accordingto specifications. In addition, shaking in the incubator may stop whenplates are being loaded in that incubator or others in the incubatorstack. Suitable incubators are known in the art, and available, forexample, from Stratec Biomedical Systems AG of Germany.

Next to the incubator station are one or more washing stations 228. Thewashing stations 228 are provided to add wash buffers to the samples andaspirate unwanted fluid. Each washing station may include a sample platemount, which may have an integrated shaker, one or more wash bufferdispensers, and one or more aspirators. One or more magnets may bemounted on a movable magnet plate located below the sample plate mount,and the magnet plate may be selectively moved upwards towards themulti-well plate 206 to attract paramagnetic beads in the specimens.Suitable wash stations are known in the art, and available, for example,from Stratec Biomedical Systems AG of Germany.

A luminometer 230 or other test apparatus (such as a fluorometer orcombined luminometer/fluorometer) may be mounted in the housing 124,such as below the pipette tip input 108. The luminometer 230 is adaptedto detect a light signal that indicates the presence of one or moreviral DNA strands or other signal indicia to determine the presence orabsence of a virus or other condition in the patient. Suitableluminometers are known in the art, and available, for example, fromStratec Biomedical Systems AG of Germany.

The design of plate movers, pipettors, incubators, shakers, washstations, luminometers, and other automated processing equipment isgenerally known in the art, and the details of such designs do not formany part of the invention. As such, these details are not describedhere.

It has been found that the AS 100 can be configured to provide severalsignificant advantages over typical sample processing systems. Inparticular, the AS 100 includes modular components, such as reagentpacks and the like, that can be replaced so that the AS 100 can processsamples according to various different protocols. The exact processingsteps and reagents can be selected according to the particular protocolscalled for by the sample, and additional processing stations may beadded as necessary to accommodate additional assay steps. Existingprocessing stations can simple be ignored if they are not needed for aparticular assay. In addition, multiple identical stations may beprovided where simultaneous processing is desired.

The AS 100 also can be configured to process multiple different assayssimultaneously. For example, a single multiple-well plate provided inthe first sample bay 102 may include samples that require processingaccording to slightly different reagent mixtures, in which case the AS100 may be programmed to deposit the required reagents in eachparticular well. This operation can be facilitated by creating acomputer file with a map that identifies the type of sample in eachplate well, associating this file with the plate using a barcode orother identifier, and reading the barcode before or while the plate isprocessed in the AS 100.

The exemplary AS 100 also includes first and second sample bays 102, 104that are configured to receive samples in different formats (e.g., indifferent containers, in different collection media, in different stagesof processing, etc.). The first sample bay 102 receives samples providedin a 96-well plate format, and the second sample bay 104 receivessamples provided in individual sample containers. This arrangement hasbeen found to be particularly useful in the context of conventional HPVtesting processes. Many HPV tests are conducted on the portion of acervical sample that remains after a pap smear test is conducted. Often,relatively little patient tissue is left in such liquid-based cytologysample containers, and it may be necessary to process the remainingsample to make it suitable for HPV testing. Typical processing stepsinclude centrifugation of an aliquot of the remaining sample to pelletthe cells, removal of the LBC medium, and processing of the cells toobtain nucleic acid samples. The resulting processed samples typicallyhave relatively little volume, and often are collected into a sampleplate having many samples from many different patients. What is left ofthe original sample usually is archived in case further tests arerequired. An automated system for preparing such nucleic acid samples inmulti-well plates is described in U.S. application Ser. No. 12/588,304,which is incorporated herein by reference in its entirety. In othercases, cervical samples may be collected specifically for HPV testing(or with HPV testing being the primary test). An example of such acollection process involves the digene HPV Test Kit, which may use acervical brush to collect a cervical sample in a vial containing thedigene Collection Medium (“DCM”), both of which are available throughQiagen. The sample container 506 illustrated in FIG. 5 is one example ofsuch a container. Samples taken specifically for HPV testing may containa relatively large amount of testable tissue, and may be tested for HPVwith relatively little pre-processing, particularly when compared toremainder samples from pap smear tests. To account for these differentsample sources and formats, the first sample bay 102 may receivepre-processed cervical samples (i.e., samples that have been processedto provided purified nucleic acid which may be in a different mediumthan their original collection medium), and the second sample bay 104may receive unprocessed cervical samples (i.e., samples provided in asample collection medium).

Despite the differences between samples developed from pap smear sampleremainders and samples taken specifically for HPV testing, the exemplaryAS 100 is able to process both sample types. Further, the AS 100 may beconfigured to process both sample types simultaneously, and withoutinterrupting the machine's operation. Providing two separate sample baysfacilitates this operation by providing sample inputs configured toreceive specific sample formats, but it would be possible in otherembodiments to provide a single sample bay adapted to receive multiplesample formats. Multiple-format processing may, in some circumstances,provide a significant benefit over typical processing systems that relyon uniformity in the samples to operate properly and continuously. Inother embodiments, further flexibility may be provided by adding morebays or adapting existing bays to receive samples in further formats.Despite the advantages possible from simultaneously processing bothsample types, this ability may not be necessary where samples areprovided largely in one format or the other, or where single-formatmachines are otherwise desired. As such, other embodiments may beconfigured such that there is only a single sample bay, or so thatmultiple sample bays receive samples in substantially the same format.

The illustrated embodiment may operate, in general terms, byconsolidating specimens (i.e., patient samples and controls orcalibrators, where desired) into a multi-well plate, and then processingand testing the samples collectively. Some or all of the specimens in asingle plate may be provided when the plate is initially entered at thefirst sample bay 102. In other cases, the specimens may instead oradditionally come from the individual samples provided in the secondsample bay 104, or from the controls and calibrators found in thecontrol bay 106. Specimens provided from the second sample bay 104 orcontrol bay 106 may require additional processing before they are placedin the multi-well plate, but this is not required in all embodiments.While the many specimens in a single multi-well plate may come fromvarious different sources, they all may be processed according to thesame protocol. Alternatively, the protocols for the different samplesmay differ somewhat, in which case the AS 100 is programmed to track thekind of sample in each well, and treat them disparately as necessary tofollow the specified protocols. For example, the pipettors 216 maydispense different reagents or different amounts of reagents in thedifferent specimens types, or the washing stations 228 may dispensesomewhat different wash buffers in each specimens type. Ultimately, allof the specimens in a single multi-well plate are tested and returned tothe first sample bay 102 for removal. While the foregoing consolidationregime is believed to be helpful in at least some embodiments, in otherembodiments, separate multi-well plates may be used for samples providedin the second sample bay 104 or for controls and calibrators. In stillother embodiments, an AS 100 may be capable of mixing samples in asingle plate, but operated so that it does not do so. This may be done,for example, where samples of only one type are available, wheredifferences in assay protocols can not be conveniently accommodated (forexample, assay differences such that a single unified protocol may bedifficult to design or inefficient to run), or where samples of one typeare provided in completely filled plates.

A general process flow for an embodiment may begin by querying all ofthe system resources to determine the kinds of samples loaded into thesystem and the amount of supplies available to process those samples.Next, the system may prepare a processing plan, and begin schedulingresupply instances. Where samples of two different types are available,the system may process them separately or consolidate them as processingoccurs. For example, the system may fill empty wells on each multi-wellplate provided in the first sample bay 102 with any available samples inthe second sample bay 104. Of course, a user also may providepreferences as to how to process mixed sample supplies.

An exemplary processing method is now described with respect to the flowpath 900 illustrated in FIG. 9. In this embodiment, the AS 100 isequipped to perform assays to determine the presence of HPV in humancervical samples, but this use is only exemplary. The illustrated flowpath begins after the machine has been loaded with sufficient samples,reagents, and other consumables to begin processing. In this example,the flow path is provided from the standpoint of specimens drawn frompatient samples provided in sample containers at the second sample bay104, but some of the specimens may be calibrators or positive and/ornegative controls processed in parallel with patient samples. At step902, the specimens are mixed by mechanical agitation of theircontainers, by pipetting action, or both. Mixing may be optional,depending on the type of specimen. For example, mixing may be desirablefor samples comprising intact cells, or cells that have been stored in abuffer than can cause cell lysis. Also, mixing may be performed beforethe samples are loaded in the second sample bay 104. For example,individual samples, or multiple samples loaded in one or more sampleracks, may be mounted on a shaker platform that mixes the samples (e.g.,for about 2 minutes) before they are placed in the AS 100.

In step 904, the pipettor 216 transfers an aliquot of each specimen(whether it is a patient sample or a control/calibrator) to a multi-wellplate 206 located at a preparation station (e.g., station 212 or station214). The plate 206 may be positioned at the station by the plate mover204 as part of the initial process setup, or placed manually by anoperator. If the plate mover 204 is used to place the plate 206 at theprocessing station, the plate mover 204 may move on to perform othertasks while the plate is filled with specimens.

The multi-well plate 206 may be empty when it is placed on the station,or it may include other specimens initially provided in the multi-wellplate 206 when it was installed in the first sample bay 102. Suchspecimens may be produced by a pre-analytical system, as describedelsewhere herein. Where it is desired to process only specimensinitially provided in the multi-well plate 206 (i.e., where it is notdesired to process specimens taken from the second sample input 104 orcontrol bay 106), steps 902 and 904 may be optional or omitted.Nevertheless, a mixing step may still be desired for specimens initiallyprovided in a multi-well plate. In order to provide some redundancy andthe ability to retest specimens, an additional step may be provided inwhich a portion of each specimen in a plate is transferred to a secondmulti-well plate. This may be particularly useful for samples initiallyprovided in the plate, as it may be relatively cumbersome to obtain aduplicate of those samples if additional testing is required (additionalsamples can more easily be taken from the sample containers already inthe second sample bay 104). While the multi-well plate 206 may beentirely filled with specimens in step 904, some wells may remainunfilled.

At step 906, the pipettor 216 draws a denaturation reagent from areagent reservoir 702 and adds the denaturation agent to each specimen.Specimens may be provided in a collection medium comprising 1.0% NP-40,0.25% sodium deoxycholate, 50 mM Tris-HCl, 25 mM EDTA, 150 mM NaCl, andbetween 0.05% and 0.09% sodium azide. The denaturation reagent maycomprise, for example, for a 50 microliter sample, about 25 microlitersof about 1.75 N NaOH or another denaturation reagent. Oil may be addedto each well during this step and may again be added to each well aftersubsequent aspirations, which may prevent evaporation and promotegreater temperature uniformity. The oil may be silicone oil. The oil mayhave a viscosity of about 5 cSt. The multi-well plate 206 is thentransported by the plate mover 204 to a first position in the incubator226, and incubated for about 30 minutes at about 70° C. with optionalshaking.

At step 908, the plate mover 204 transports the multi-well plate to asample preparation station, and the pipettor 216 withdraws an RNA probefrom another one of the reagent reservoirs 702 and adds the RNA probe toeach specimen. The RNA probe may be provided at concentration of about375 ng/ml in a probe diluent. The RNA probe may comprise one or more HPVgenomic sequences or a subsequences thereof, which may specificallyhybridize to one or more high-risk HPV subtypes associated with elevatedrisk of cervical cancer, such as types 16, 18, 26, 31, 33, 35, 39, 45,51, 52, 56, 58, 59, 66, 68, and 82, or a subset of these high-risktypes, such as types 16, 18, and 45. Exemplary RNA probes comprising HPVgenomic sequences are described in HPV U.S. patent application Ser. No.12/605,605, filed Oct. 26, 2009, which is incorporated by referenceherein in its entirety. The probe may be provided in a probe diluentcomprising 2.2 M BES (N,N-Bis(2-hydroxyethyl)-2-aminoethanesulfonicacid), 2.6% polyacrylic acid (PAA), 0.7 N NaOH and between 0.05% and0.09% sodium azide. Preferably the probe diluent has a viscosity thatfacilitates more accurate dispensing by automatic pipetting techniques,such that the desired volume can be accurately and automaticallypipetted. If the viscosity is undesirably low, the probe diluent may beunable to form a stable drop; conversely, if the viscosity isundesirably high, the probe diluent drop may be too large and may causesignificant disturbance of the contents already in the sample (e.g., bysplashing). The plate mover 204 then moves the multi-well plate 206 to asecond position in the incubator 226 where the specimens are incubatedfor about 22 to about 30 minutes at 69.5° C. with optional shaking.

At step 910, the plate mover 204 transports the multi-well plate 206 toa sample preparation station, where 25 microliters of capture beadsuspension are added by the pipettor 216 from another reagent reservoir702. Exemplary capture beads may be paramagnetic beads comprisingpolystyrene, may have a diameter of about 1 micrometer, and may becoupled to an antibody via an1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDAC)linker. Another exemplary capture bead that may be used is approximately1 μm carboxylated SERADYN beads, available from Thermo Fisher. Thecapture beads also may comprise a monoclonal anti-RNA-DNA hybridantibody derived from a hybridoma cell line is used, such as thosedescribed in U.S. Pat. Nos. 4,865,980, 4,732,847, and 4,743,535, thecontents of each of which are incorporated herein by reference in theirentirety. Hybrid-specific monoclonal antibodies may be prepared usingtechniques that are standard in the art. The hybrid-specific monoclonalantibody may be used for both capturing and detecting the target nucleicacid. The capture beads may be contained in a buffer comprising 6%casein, 100 mM Tris-HCl, 300 mM NaCl, and 0.05% sodium azide. Themulti-well plate 206 is then transported by the plate mover 204 to athird position in the incubator 226 where the specimens are incubatedfor 30 minutes at 69.5° C. with optional shaking.

At step 912, the plate mover 204 transports the multi-well plate 206 toa wash station 228, where a plate of magnets is raised into positionbelow the multi-well plate 206 to attract the paramagnetic beads forabout 2-3 minutes, after which unbound liquid is aspirated. The washstation 228 may optionally shake the plate during the magneticattraction and/or aspirating processes.

Next, the plate mover 204 transports the multi-well plate to a samplepreparation station for step 914 in which a labeled antibody is added bythe pipettor 216 from another reagent reservoir 702. The labeledantibody may comprise a monoclonal anti-RNA-DNA hybrid antibody(examples of which are described above) which may be directly orindirectly coupled to a detectable label. The labeled antibody may beprovided in a buffer comprising 100 mM TrisHCl, pH 7.4, 0.5 M NaCl, 0.1mM ZnCl₂, 1.0 mM MgCl₂, 0.25% Tween 20, 0.2 mg/ml RNase A, 4%hydroxypropyl-b-cyclodextrin (cyclodextrin), 30% bead dilution buffer asdiscussed previously, 0.05% goat IgG, between 0.05% and 0.09% sodiumazide. The label may comprise an alkaline phosphatase. The multi-wellplate 206 is then transported by the plate mover 204 to another stationin the incubator 226, where in the specimens are incubated for about 30minutes at about 45° C. with optional shaking.

At step 916, the plate mover 204 transports the multi-well plate 206back to the wash station 228 (or to another wash station), where beadsare again attracted to magnets for about 2-3 minutes, after whichunbound liquid is aspirated, with optional shaking. After aspiration, awash routine is conducted. The wash routine comprises: moving themagnets away from the multi-well plate to free the magnetic beads,adding 300 microliters of a wash solution, allowing the wash solutionand beads to incubate for about 3 minutes with optional shaking, afterwhich beads are attracted with magnets for about 2-3 minutes, and theunbound liquid is aspirated. The wash routine is carried out about twoto three times with a first wash solution containing detergent, then onetime with a second wash solution that is free of detergent. An exemplaryfirst wash solution comprises 40 mM Tris, pH 8.2, 100 mM NaCl, 0.5%Triton-X 100 and between about 0.05% and about 0.09% sodium azide, andan exemplary second wash solution comprises 40 mM Tris, pH 8.2, 100 mMNaCl, and between about 0.05% and about 0.09% sodium azide.

The plate mover 204 then transports the multi-well plate 206 to a samplepreparation station for step 918, in which 40 microliters of aluminescence substrate is added. Exemplary luminescence substratesinclude LUMI-PHOS 530 reagent (Lumigen, Detroit, Mich.), DR2 (AppliedBiosystems, Foster City, Calif.), and CDP-Star® with Emerald-II™Enhancer (a dioxetane-based substrate, available from AppliedBiosystems). The multi-well plate 206 then is transported by the platemover 204 to another station in the incubator 226 where the specimensare incubated for about 10-15 minutes at about 15-30° C. with optionalshaking.

At step 920, the plate mover 204 transports the multi-well plate 206into a luminometer 230. The luminometer evaluates the luminescence ofeach sample, as known in the art. Luminescence may be measured, forexample, in relative luminescence units (RLUs), which may be transmittedto an on-board controller and/or to a central control unit. Luminescencevalues may be computationally processed to indicate the presence orabsence of an analyte in the samples. For example, an HPV assay may beperformed in which an assay positive standard containing 1 pg/ml of HPVDNA is used to establish the luminescence corresponding to a positivecutoff. Sample RLU values are then divided by the RLU value for thepositive standard creating a RLU/CO (RLU to cutoff value). Results arereported in RLU/CO and values greater than or equal to a giventhreshold, such as 1.0, can be considered positive. Alternatively,ranges of RLU/CO values may be established that are considered to benegative, indeterminate, or positive. After testing, the plate mover 204transports the multi-well plate 206 to the first sample bay 102 forremoval by the operator. The first sample bay 102 may have multipleplate positions, so that several processes plates can accumulate beforebeing unloaded.

In the foregoing embodiment, it will be understood that some specimensmay be processed at the same time according to alternative assayprotocols that vary from the foregoing protocols. Thus, some specimensmay receive different reagents or skip reagent addition steps. However,due to the specimens all being on the same multi-well plate 206, theyall will be incubated and shaken together.

In steps involving dispensing samples, controls, calibrators or reagents(e.g., steps 904, 906, 908, 910, 914, 916, and 918), a pipette tip isaffixed to a pipettor, an aliquot is drawn from a sample or sufficientreagent is drawn into the pipette tip for multiple samples, the pipettetip is positioned over each a plate well and the desired volume ofsample or reagent is dispensed. To prevent cross-contamination, pipettetips used for dispensing reagents do not contact any specimens duringordinary use. Where even greater control over cross-contamination isdesired, a single pipette tip may be used to dispense reagent into onlya single specimen, after which the pipette tip is discarded or washedand reused. Reagents also may be drawn from a reservoir into a fluidpath, and dispensed from a re-useable nozzle. To preventcross-contamination, a re-useable nozzle typically does not contactsamples during ordinary use. A re-useable nozzle may be periodicallywashed and/or flushed to further decrease the likelihood ofcross-contamination and prevent buildup of reagent residue. Dedicatedaspirators, such as aspirators used in the wash stations 228, may beperiodically washed in a fluid bath, or operated such that they do notneed cleaning, as known in the art.

Whether the reagent dispenser is a pipette tip or nozzle, multiplechannels may be used for concurrent dispensing, thereby decreasingprocessing time and potentially improving throughput. Multiple channelsmay be spaced to match the distance between adjacent plate wells, or awhole multiple of this distance, so that each dispensing pipette tip ornozzle is always positioned over a well For example, if the spacingbetween pipette tips or nozzles is twice the distance between wells, an8-well row of a plate can be filled by moving the pipette tips/nozzlesover four of the wells, dispensing, moving the pipette tips/nozzles overthe other four wells, and dispensing. This achieves complete dispensingfor each row in two dispensing steps and with very little extraneousmovement.

Though this example is described with respect to particular reagents,volumes, incubation times, temperatures and processing steps, thesevariables and steps may be varied within the scope and spirit of theinvention. For example, samples within a single multi-well plate mayhave different reagents added or different volumes of reagents addedthan other samples in the same multi-well plate. More or fewer than thesteps recited in this example may be performed, and steps may berepeated, omitted, and/or replaced. Additionally, other denaturationreagents, buffers, wash solutions, probes, probe diluents, capturebeads, capture bead buffers, labeled antibodies, labeled antibodybuffers, luminescent substrates, incubation times, and incubationtemperatures may be used, including, for example, those described inU.S. Ser. Nos. 12/605,605 or 12/605,540, and others, such as thosedescribed in Sambrook et al., Molecular Cloning: a laboratory manual,3rd Edition Cold Spring Harbor Laboratory Press, CSH, New York, 2001;Sambrook et al., Molecular Cloning, A Laboratory Manual (2nd Ed.), ColdSpring Harbor Laboratory, Cold Spring Harbor, N.Y., 1989; CurrentProtocols in Molecular Biology, F. M. Ausubel et al., eds., CurrentProtocols, a joint venture between Greene Publishing Associates, Inc.and John Wiley & Sons, Inc., (including supplements); Ausubel et al,Short Protocols in Molecular Biology, John Wiley and Sons, 1992), eachof which is incorporated by reference herein in its entirety.

As noted above, the plate mover 204 may be free to perform otherprocesses while certain steps are being performed. In addition, some orall of the various steps of the process may be performed substantiallysimultaneously by providing sufficient processing stations and equipmentin the housing 124. For example, one plate 206 may be filled in step904, while another is being aspirated in one wash station 228 in step912, while another is being washed in another wash station 228 in step916. At the same time, several plates may be in various positions withinthe incubator 226, and another may be being transported betweenoperations. Other simultaneous operations may be occurring as well. Toaccommodate simultaneous operation, redundant processing stations andequipment may be provided. For example, each wash station 228 may beequipped to perform either step 912 or step 916. As another example,where one process may take significantly longer than others, multipleprocessing stations may be provided for that process and operated on astaggered cycle to increase the frequency at which plates complete thatparticular process, and maintain the flow path 900 at a faster pace.

At the end of the testing process described above, a CCU associated withthe AS 100 may evaluate the results to determine whether they arereliable, such as by confirming that positive and negative controls donot indicate a processing problem. The CCU also may evaluate each testedspecimen to determine whether the test result is negative or positive,and store this information with the sample identification number forlater use to report test results and so on.

The CCU also may determine whether any of the specimens require furthertesting to validate the initial test (such as by simply retesting thesample), or provide more information about the test results. Forexample, where an HPV test is being conducted, a first assay may usechemiluminescence for the qualitative detection of multiple high riskgenotypes, and a reflex assay may determine the presence of particulargenotypes. Examples of HPV assays that may be used in this manner arethe digene eHR HPV DNA Test, which identifies fifteen high risk HPVgenotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and82), and the digene eHR HPV 16 18/45 DNA Test, which detects thepresence of genotypes 16, 18 and 45. Both of these tests are availablefrom Qiagen, as noted above. While a full panel test may be followed byreflex testing, as described above, some samples may be reflex tested atthe outset. This may be appropriate, for example, where abnormal cellsare observed in a pap smear, suggesting that full panel testing can bebypassed. At the end of the above testing process 900, the CCU may queryeach sample's test schedule to determine whether additional testing iscalled for after receiving a particular result (which may be a positiveresult or a negative result), and identify each sample that matches theretest criteria.

The retesting process may be different for samples provided inindividual sample containers in the second sample bay 104 andpre-processed specimens provided in multi-well plates in the firstsample bay 102. As noted above, samples in the second sample bay 104 maycomprise original samples collected primarily for the particular testbeing performed in the AS 100, and sufficient volume may remain in eachsample container to allow subsequent testing. Thus, it may be possibleto retest these original samples with relative ease. Specimens providedin multi-well plates, one the other hand, may comprise pre-processedportions of original samples that are not suitable for testing usingwithout some processing. Furthermore, the amount provided in themulti-well plate may be insufficient for multiple tests. As such, if aretest is required for a specimen provided in a multi-well plate orother small-volume container, it may be necessary to process anotherspecimen from the original sample container into a testable formatbefore beginning the retest. It may be possible to avoid this additionalstep by generating multiple specimens from each sample, or, if thespecimens in the multi-well plate have sufficient volume, removing aportion of each plate specimen to a redundant plate used for retesting.It is also envisioned that some samples initially provided as specimensin a multi-well plate may actually be testable without whateverpre-processing was used to generate the plate specimen. In such cases,retesting may be performed by simply placing the original samplecontainer in the second sample bay 104. Also, in some cases it may bepossible to recondition samples that have been processed and tested inthe luminometer to be retested.

Retests may be performed in substantially the same way as the aboveprocess, but with any necessary variations to accommodate anydifferences between the initial test and retest protocols. In anembodiment performing HPV testing, the CCU may identify the samplesrequiring retesting to the operator via a graphical user interface or bya printed test result form. The operator may remove the retest samplesfrom the second sample bay 104, mix them using a vortexer (if mixing isnot done in the AS 100) and replace them in the AS 100 on one or moresample racks. For specimens provided on multi-well plates, the user mayprocess additional retest specimens into a new multi-well plate andplace them in the first sample bay 102. Where necessary, the operatoralso may load and mix the appropriate retest reagents, controls andcalibrators into the AS 100. The samples are then processed according tothe retesting protocol.

The retest protocol may include one or more retest assays. For example,in an embodiment in which samples are tested for HPV 16, 18 and 45genotypes, a first specimen may be taken from each sample and tested forthe HPV 16 genotype, and a second specimen may be taken from each sampleand tested for the HPV 18 and 45 genotypes. These retests may beperformed sequentially, or, if the AS 100 has sufficient equipment andresources, at the same time. In this embodiment, multiple retestspecimens may be drawn separately from each sample container in thesecond sample bay 104, and multiple retest specimens from each samplemay be provided in a multi-well plate loaded into the first sample bay102. Of course, only a single specimen may be provided for single-assayretests, and more specimens may be provided if further tests areindicated. As with the process described earlier herein, test resultsmay be collected and processed by a suitable CCU, and reported asnecessary.

Embodiments of the AS 100 may use barcodes or other tracking systems(e.g., radio frequency identification (“RFID”) chips, and the like) toassist with sample and resource tracking. For example, each sample plate400 may be barcoded, and that barcode can associate each plate well witha particular sample in a plate “map.” The sample information mayinclude, for example, the patient's identity, the requested testprotocol(s), and a history of any prior processing activities. The platebarcode may be read by a handheld scanner before it is placed in the AS100, and scanned again by a fixed scanner inside the AS housing 124 asit is picked up from the first sample bay 102 by the plate mover 204.Similarly, each individual sample container 506 may be barcoded andassociated with patient and processing information. The samplecontainers may be scanned before or as they are inserted into the AS100, by a handheld scanner or a scanner located inside the second samplebay 104. As noted above, the sample rack 500 also may include barcodeinformation. Reagents, controls and calibrators also may be barcoded totrack their use, and provide a history of which reagents were used withwhich samples. At any time a barcode does not match expected values, theAS 100 may require user input to correct the error. For example, the AS100 may require hand scanning for an unread barcode, or removal orreplacement of a reagent or sample that is not properly loaded in the AS100. Barcodes also may be used to ensure that samples requiring certainreagents or other processing steps are not inadvertently loaded when theAS 100 is not set up to process those samples. Additional barcodereaders may be placed at various locations throughout the AS 100 toensure quality control. For example, a barcode on a sample plate 400 maybe scanned just prior to the luminometer entrance to confirm that eachplate tested in the luminometer is known and accounted for. Testedplates may be rescanned a final time as they are replaced in the firstsample bay 102 to record their completed processing.

In addition to tracking the presence and kind of reagents, embodimentsof the AS 100 may track expiration and lot codes provided in reagentbarcodes. Tracking this information permits the system to monitor thereagents to ensure that expired reagents are not used, and providewarnings before fluid supply containers need to be changed. Thistracking also allows operators to use a random selection of reagentsthat may have different expiration dates, without having to manuallytrack the expiration dates. Automated expiration date tracking and theability to quickly load new reagents without interrupting operation alsoalleviates the need to schedule downtime to replace reagents.

It may be necessary or desirable to calibrate the AS 100 from time totime to ensure that it is working properly and within desired operatingparameters. The calibration process may be performed using any suitablecalibrators. As noted above, the AS 100 may include a dedicated controlbay 106 into which calibrators are loaded. In this embodiment,calibration may be performed by pipetting the calibrators into emptyplate wells on a plate that has samples in other wells, or adding thecalibrator to an empty plate used only for calibration. Those wells areprocessed according to the necessary protocols, along with the remainingwells on the plate (assuming the remaining wells have samples in them).Calibrators also may be provided in a plate that is installed into thefirst sample bay 102, or in a sample container installed into the secondsample bay 104. For example, where a pre-analytical processing system(“PAS”) is used to prepare a multi-well plate with samples, that systemmay create a calibrator sample to help calibrate the AS 100.Additionally, the PAS may create a control sample to help determinewhether the pre-analytical system and AS 100 are working withinspecifications.

The AS 100 may use any suitable calibration strategy. For example, thesystem may be calibrated at set time intervals, at set processingintervals, upon the occurrence of particular events, or according othercriteria or a combination of criteria. For example, in one embodiment,calibration may be performed at the beginning of each daily shift, andwhenever a new reagent pack from a new lot is introduced to the system(adding reagents from a new container that originated from the samereagent lot may not require calibration). Calibration also may berequired upon the expiration of a reagent pack's in-use life, regardlessof whether it is fully consumed or not. Expiration dates for reagentscan be tracked using barcodes or other indicia.

In another exemplary embodiment, calibration may be performed for eachmulti-well plate processed by the system. In this embodiment, one ormore wells should be left unfilled by the technician or PAS preparingthe plate. Using per-plate calibration may help reduce the incidence offailed sample tests (i.e., tests performed while the machine was notwithin calibration specifications), but may reduce overall efficiency bytaking up plate resources. However, where the plates are prepared by aPAS, the PAS may be programmed to leave empty wells on each plate topermit the AS 100 to calibrate whenever necessary without having to usea dedicated calibration plate.

In addition to calibration, the AS 100 may include a control regime tohelp ensure quality control and detect contamination. For example,positive controls may be used to monitor assay performance, and negativecontrols may be used to detect well-to-well or cross-contamination.Where the AS 100 is adapted to process samples using differentcollection media or pre-processing steps, it may be necessary to includemultiple positive or negative controls corresponding to each samplecondition. For example, samples arriving in a multi-well plate in thefirst sample bay 102 may include a mixture of samples extracted fromdifferent liquid based cytology media (e.g., SurePath™ samples as knownand available from BD Diagnostics of Burlington, N.C. and PreservCyt™samples as known and available from Hologic Inc. of Marlborough, Mass.),in which different controls may be used on the plate to ensure accuracywith respect to both kinds of sample. Alternatively, a single controlmay be used for a number of different sample types, as dictated by thecircumstances. Controls may be provided in the control bay 106 or thesecond sample bay 104, as described above, or they may be added to amulti-well plate before it is installed in the AS 100. For example, aPAS could add any necessary controls.

Embodiments of an AS 100 may be operated substantially continuously forrelatively long periods to provide ultra-high fully automatedthroughput. As explained and illustrated above, the system may includemultiple redundant inputs to receive first and second sample types, aswell as multiple redundant pipette tip supplies, reagent packs, andcontrol/calibration/oil cartridges. The system also includes redundantwaste fluid receptacles and a solid waste receptacle with anintermediate chamber that can collect waste even when the mainreceptacle is being emptied. Thus, each consumable or processedcomponent can be removed and replaced while a redundant system orcomponent is operating. As such, the system may be fully-automated andoperable continuously for as long samples and supplies are beingprovided. The system also may include features such as automated reagentmixing and pierceable containers to reduce manual labor to virtuallynil.

In one exemplary embodiment, an AS 100 was prepared to operate in afully-automated mode to perform HPV tests on samples provided in QiagenDCM collection tubes that were directly loaded into the second samplebay 104, and up to fifteen plates (having up to 1440 samples) processedfrom liquid based cytology media loaded into the first sample bay 102.The AS 100 fully automated all steps from reagent and sample loading tothe final data acquisition. The assay time to the first result wasreduced at least by 40% compared to manually performing the HC2® HPV DNATest from Qiagen. The AS 100 detected up to fifteen different high riskHPV genotypes, and had an analytical sensitivity of 1875 copies (95% CI1615-2290) of HPV 16 plasmid. Assay specificity was evaluated with 13HPV low risk types. All HPV low risk types were tested at a highconcentration of 2×10^8 copies/ml, and there were no false positiveresults. The assay reproducibility on the AS 100 was significantlyimproved over the manual assay using HPV 16 plasmids. The fullyautomated assay achieved consistent performance within plate, from plateto plate, day to day and instrument to instrument. No indication oftarget carryover was found when samples containing up to 10^9 copies/mlof HPV DNA type 16 were processed on the exemplary AS 100.

The above example may be operated to provided extremely high throughput.As many as 5,000 or more assays of a single type can be run in a singleday. Alternatively, the it may be possible to reconfigure such anembodiment (e.g., by simply loading the appropriate reagents), tosimultaneously or consecutively run ten to twelve different assays, with25-30 tests being conducted according to each assay every day. Ifnecessary the reagent or sample bays may be modified to hold thenecessary reagents and samples. The ultra-high output of these exemplaryembodiments is also particularly beneficial considering the relativelysmall size of the apparatus. When measured in output per square foot offloor space, the throughput is particularly high. Nevertheless, whilehigh out put may be obtained using embodiments of the invention, it isnot required in all embodiments, and many benefits and advantages may beavailable even in small-scale or low output embodiments.

While the invention has been described by way of examples and preferredembodiments, it is understood that the words which have been used hereinare words of description, rather than words of limitation. Changes maybe made, within the purview of the appended claims, without departingfrom the scope and spirit of the invention in its broader aspects.Although the invention has been described herein with reference toparticular means, materials, and embodiments, it is understood that theinvention is not limited to the particulars disclosed. The inventionextends to all equivalent structures, means, and uses which are withinthe scope of the appended claims.

1. A reagent cabinet for an automated processing apparatus, the reagentcabinet comprising: a housing; a drawer slidably mounted in the housingand movable between a first position in which the drawer is containedwithin the housing, and a second position in which at least a portion ofthe drawer is outside the housing, the drawer having a lower deckadapted to receive a fluid reservoir, and an upper deck located abovethe lower deck and configured to receive a fluid supply container, thefluid supply container being selectively removable from the drawerindependently of the fluid reservoir; a supply connection hoseconfigured to connect the fluid supply container to the fluid reservoir;and a reservoir connection hose adapted to selectively connect to thefluid reservoir and to convey fluid from the fluid reservoir to adownstream location outside the cabinet.
 2. The reagent cabinet of claim1, further comprising one or more doors pivotally mounted on the cabinetand configured to close the cabinet when the drawer is in the firstposition.
 3. The reagent cabinet of claim 1, wherein the upper deck isconfigured to receive a supplemental fluid supply container.
 4. Thereagent cabinet of claim 3, wherein the fluid supply container and thesupplemental fluid supply container contain the same kind of fluid. 5.The reagent cabinet of claim 3, wherein the fluid supply container andthe supplemental fluid supply container contain different kinds offluid.
 6. The reagent cabinet of claim 4, wherein the fluid supplycontainer contains a wash buffer having a detergent, and thesupplemental fluid supply container contains a wash buffer not having adetergent.
 7. The reagent cabinet of claim 1, wherein the upper deckcomprises a lower opening configured to receive an outlet from the fluidsupply container.
 8. The reagent cabinet of claim 1, wherein the upperdeck comprises a hose hook configured to hold the supply connection hosewhen the fluid supply container is not in place on the upper deck. 9.The reagent cabinet of claim 1, wherein the fluid supply container isremovable in a vertical direction from the upper deck when the drawer isin the second position.
 10. The reagent cabinet of claim 1, furthercomprising a pump configured to convey fluid through the reservoirconnection hose and to the downstream location.
 11. The reagent cabinetof claim 10, wherein the pump is mounted on the drawer.
 12. A reagentcabinet for an automated processing apparatus, the reagent cabinetcomprising: a housing having a front opening; a drawer slidably mountedin the housing and movable in a sliding direction between a firstposition in which the drawer is contained within the housing, and asecond position in which at least a portion of the drawer extendsoutside the front opening of the housing, the drawer being configured tohold one or more fluid reservoirs in a first vertical height, and tohold one or more fluid supply containers in a second vertical height,the second vertical height being higher than the first vertical height;and one or more supply connection hoses each being configured to connecta respective fluid supply container to a respective fluid reservoir;wherein the one or more fluid supply containers are selectivelyremovable from the drawer independently of the one or more fluidreservoirs to thereby permit replacement of the one or more fluid supplycontainers without removing the one or more fluid reservoirs.
 13. Thereagent cabinet of claim 12, wherein the drawer comprises a first deckconfigured to hold the one or more fluid reservoirs at the firstvertical height, and a second deck configured to hold the one or morefluid supply containers at the second vertical height.
 14. The reagentcabinet of claim 13, wherein the second deck is positioned directlyabove the first deck.
 15. The reagent cabinet of claim 13, wherein thefirst deck and the second deck are aligned in the sliding direction. 16.The reagent cabinet of claim 15, wherein the first deck and the seconddeck are positioned such that the one or more fluid supply containersare closer to the front opening of the housing than the one or morefluid reservoirs when the drawer is in the first position, and the oneor more fluid supply containers are further from the front opening ofthe housing than the one or more fluid reservoirs when the drawer is inthe second position.
 17. The reagent cabinet of claim 12, wherein theone or more fluid supply containers comprises a plurality of fluidsupply containers containing the same kind of fluid.
 18. The reagentcabinet of claim 12, wherein the one or more fluid supply containerscomprises a plurality of fluid supply containers containing differentkinds of fluid.
 19. The reagent cabinet of claim 18, wherein at least afirst fluid supply container contains a wash buffer having a detergent,and at least a second fluid supply container contains a wash buffer nothaving a detergent.